4-(N-substituted amino)-2-butynyl-1-carbamates and thiocarbamates and derivatives thereof as centrally acting muscarinic agents

ABSTRACT

4-(N-Substituted amino)-2-butynyl-1-carbamates and thiocarbamates and derivatives thereof are described, as well as methods for the preparation and pharmaceutical compositions of same, which are useful as centrally acting muscarinic agents and are useful as analgesic agents for the treatment of pain, as sleep aids and as agents for treating the symptoms of senile dementia, Alzheimer&#39;s disease, Huntington&#39;s chorea, tardive dyskinesia, hyperkinesia, mania, or similar conditions of cerebral insufficiency characterized by decreased cerebral acetylcholine production or release.

BACKGROUND OF THE INVENTION

The present invention relates to novel 4-(N-substitutedamino)-2-butynyl-1-carbamates and thiocarbamates and derivatives thereofuseful as pharmaceutical agents, to methods for their production, topharmaceutical compositions which include these compounds and apharmaceutically acceptable carrier, and to pharmaceutical methods oftreatment. More particularly, the novel compounds of the presentinvention are centrally acting muscarinic agents useful in treating thesymptoms of cognitive decline in an elderly patient.

Disorders of cognition are generally characterized by symptoms offorgetfulness, confusion, memory loss, attentional deficits and/or, insome cases, affective disturbances. These symptoms may arise as a resultof the general aging process and/or from organic brain disease,cerebrovascular disease, head injury or developmental or geneticdefects.

The general decrease in cognitive function which accompanies the agingprocess is well accepted. The same phenomenon has been observed anddocumented in many lower mammals, including those routinely employed inpharmacological testing programs for screening and predicting usefulnessfor particular drugs in higher animals, including humans.

Although disorders of cognition often accompany the general agingprocess, presenile and senile primary degenerative dementia are the mostcommon accepted causes of mental deterioration in the elderly. It hasbeen estimated that at least ten percent of persons overt sixty years ofage will eventually suffer severe mental deterioration. A much largernumber will experience cognitive decline of sufficient severity toimpede their activities.

Many of the symptoms of cognitive disorders, especially impaired memory,are associated with decreased acetylcholine synthesis and the impairmentof cholinoreceptive neurons. In the hippocampus and cerebral cortex ofpatients suffering from primary degenerative dementia for example, thelevel of the enzyme choline acetyltransferase (CAT) can be reduced asmuch as ninety percent (see Davies, P., et al, The Lancet, 2, page 1403(1976); Perry, E. K., et al, Journal of Neurological Sciences, 34, pages247 to 265 (1977); and White, P., et al, The Lancet, 1, pages 668 to 670(1977)).

Since CAT catalyzes the synthesis of acetylcholine from its precursorscholine and acetyl coenzyme A, the loss of CAT reflects the loss ofcholinergic or acetylcholine-releasing nerve endings in the hippocampusand cerebral cortex. There is abundant evidence that cholinergicterminals in the hippocampus are critically important for memoryformation.

The cholinergic hypothesis suggests that drugs which restoreacetylcholine levels or cholinergic function (i.e., cholinomimetic) areeffective in correcting this deficit in neurotransmitter chemical andprovide treatment of the memory impairment symptom of cerebralinsufficiency. Considerable biochemical, pharmacological, andelectrophysiological evidence supports the hypothesis that deficits inthe cholinergic system underlie geriatric cognitive dysfunction(Peterson, C. and Gibson, B. E., Neurobiology of Aging, 4, pages 25 to30 (1983)). Aged humans and nonhuman primates with decreased coginitionshow improved memory when they are treated, for example, withacetylcholinesterase inhibitors such as physostigmine. These agentsincrease the available supply of synaptic acetylcholine by inhibitingits hydrolysis.

Aminopyridines such as 3,4-diaminopyridine ameliorate age-relatedcognitive deficits by increasing the release of acetylcholine frompresynaptic nerve terminals, thus increasing synaptic acetylcholine (seeDavis, H. P., et al, Experimental Aging Research, 9, pages 211 to 214(1983)).

It has been known for some time that the natural alkaloid, muscarine,has the ability to act relatively selectively at autonomic effectorcells to produce qualitatively the same effect as acetylcholine. Twoother agents, pilocarpine and oxotremorine, have the same principalsites of action as muscarine and acetylcholine and are thus classifiedas having "muscarinic" action. Although these agents are of great valueas pharmacological tools, present clinical use is largely restricted tothe use of pilocarpine as a miotic agent.

Oxotremorine (1-pyrrolidino-4-(2-oxopyrrolidino)-2-butyne) wasdiscovered while exploring the pharmacologic actions of tremorine.During the course of screening drugs in mice, it was observed thattremorine (1,4-dipyrrolidino-2-butyne) produced a profound tremor of thehead and limbs lasting for more than one hour (see Everett, G. M.,Science, 124, page 79 (1956)). It was later discovered that tremorine isconverted to an active metabolite, oxotremorine, which is responsiblefor its pharmacological properties.

A series of N-(4-amino-2-butynyl)-N-alkylcarboxamides useful as centralnervous system stimulants is disclosed in U.S. Pat. No. 3,354,178.

A series of N-(4-amino-2-butynyl)imides useful as central nervous systemstimulants and depressants is disclosed in U.S. Pat. No. 4,065,471.

Further, derivatives containing a 2-oxazolidinone group are disclosed inU.S. Pat. Nos. 3,354,178 and 4,065,471.

The central and peripheral activity of a series of acetylenic aminesrelated to oxotremorine is disclosed by Bebbington, A., et al, BritishJournal of Pharmacology 26, pages 56 to 67 (1966). The pharmacologicalproperties of additional structural modifications of oxotremorine aredisclosed by Neumeyer, J. L., et al, Journal of Medicinal Chemistry 10,pages 615 to 620 (1967).

However, none of the compounds disclosed in the aforementionedreferences suggests the combination of structural variations of thecompounds of the present invention described hereinafter. Furthermore,the aforementioned compounds are not disclosed for treating the symptomsof cognitive decline in an elderly patient.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a compound of Formula I ##STR1##wherein R is alkyl of from one to six carbon atoms,

alkyl of from one to six carbon atoms substituted with hydroxy or alkoxyof from one to four carbon atoms,

alkenyl of from two to six carbon atoms,

alkenyl of from two to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkynyl of from two to six carbon atoms,

alkynyl of from two to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

cycloalkyl of from three to six carbon atoms, ##STR2## wherein n is zeroor an integer of one to eight and R⁴ and R⁵ are independently hydrogen,fluorine, chlorine, bromine, hydroxy, alkyl of from one to three carbonatoms, or alkoxy of from one to four carbon atoms, or ##STR3## whereinR⁴ and R⁵ are as defined above;

X is oxygen or sulfur;

R¹ is hydrogen,

alkyl of from one to six carbon atoms,

alkyl of from one to six carbon atoms substituted with hydroxy or alkoxyof from one to four carbon atoms,

alkenyl of from three to six carbon atoms,

alkenyl of from three to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkynyl of from three to six carbon atoms,

alkynyl of from three to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

cycloalkyl of from three to six carbon atoms, or ##STR4## wherein n, R⁴and R⁵ are as defined above; R² and R⁵ are each independently

hydrogen,

alkyl of from one to twenty carbon atoms,

alkyl of from one to twenty carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkenyl of from three to twenty carbon atoms,

alkenyl of from three to twenty carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkynyl of from three to twenty carbon atoms,

alkynyl of from three to twenty carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

cycloalkyl of from three to eight carbon atoms, phenyl,

phenyl substituted with alkyl of from one to four carbon atoms, alkyl offrom one to four carbon atoms substituted with hydroxy or alkoxy of fromone to four carbon atoms, alkoxy of from one to four carbon atoms,chlorine, bromine, hydroxy, nitro or trifluoromethyl or

R² and R³ are taken together with the nitrogen atom to which they areattached to form a ring denoted by ##STR5## wherein R⁵ is hydrogen,alkyl of from one to ten carbon atoms, alkyl of from one to ten carbonatoms substituted with hydroxy or alkoxy of from one to four carbonatoms, alkenyl of from two to ten carbon atoms, alkenyl of from two toten carbon atoms substituted with hydroxy or alkoxy of from one to fourcarbon atoms, alkynyl of from two to ten carbon atoms or alkynyl of fromtwo to ten carbon atoms substituted with hydroxy or alkoxy of from oneto four carbon atoms and n is as defined above, ##STR6## wherein X is asdefined above or ##STR7## wherein R⁷ is hydrogen or alkyl of from one tosix carbon atoms, or a pharmaceutically acceptable acid addition saltthereof.

As centrally acting muscarinic agents, the compounds of Formula I areuseful as analgesic agents for the treatment of pain in mammalsincluding man, as sleep aids, and as agents for treating the symptoms ofsenile dementia, Alzheimer's disease, Huntington's chorea, tardivedyskinesia, hyperkinesia, mania or similar conditions of cerebralinsufficiency characterized by decreased cerebral acetylcholineproduction or release.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.

Finally, the present invention is directed to methods for production ofa compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "alkyl" means a straight orbranched hydrocarbon radical having from one to twenty carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,hexadecyl, heptadecyl, octadecyl, nonadecyl, eicodecyl, and the like.

The term "alkenyl" means a straight or branched unsaturated hydrocarbonradical having from two to twenty carbon atoms and includes, forexample, ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl,2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl,1-tridecenyl, 1-tetradecenyl, 1-pentadecenyl, 1-hexadecenyl,1-heptadecenyl, 1-octadecenyl, 1-nonadecenyl, 1-eicodenyl, and the like.

The term "alkynyl" means a straight or branched triple bondedunsaturated hydrocarbon radical having from two to twenty carbon atomsand includes, for example, ethynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,3-heptynyl, 1-octynyl, 2-octynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl,4-nonynyl, 1-decynyl, 2-decynyl, 2-undecynyl, 3-undecynyl, 3-dedecynyl,3-tridecynyl, 1-tetradecynyl, 3-tetradecynyl, 3-pentadecynyl,3-hexadecynyl, 1-heptadecynyl, 3-octadecynyl, 3-nonadecynyl,3-eicodecynyl, and the like.

The term "alkoxy" means alkyl-0- of from one to four carbon atoms asdefined above for "alkyl."

The term "cycloalkyl" means a saturated hydrocarbon ring having three toeight carbon atoms and includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

"Halogen" is fluorine, chlorine, bromine, or iodine.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids, such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like, as well as the salts derived from nontoxicorganic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge, S. M., et al, "PharmaceuticalSalts," Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free bases for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess asymmetriccarbon atoms (optical centers); the racemates as well as the individualenantiomers are intended to be encompassed within the scope of thepresent invention.

A preferred compound of Formula I is one wherein

R is

alkyl of from one to six carbon atoms, or

alkenyl of from two to six carbon atoms;

X is oxygen;

R¹ is hydrogen, or alkyl of from two to six carbon atoms;

R² and R³ are each independently

hydrogen,

alkyl of from one to twenty carbon atoms,

alkyl of from one to twenty carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkenyl of from three to twenty carbon atoms,

alkynyl of from three to twenty carbon atoms or R² and R³ are takentogether with the nitrogen atom to which they are attached to form aring denoted by ##STR8##

wherein n is zero or an integer from one to eight, ##STR9## wherein X isoxygen or sulfur or ##STR10## wherein R⁷ is hydrogen or alkyl of fromone to six carbon atoms.

A further embodiment is a compound of Formula I in which R is methyl,ethyl, or ethenyl;

X is oxygen;

R¹ is hydrogen, methyl, or ethyl,

R² and R³ are each independently hydrogen, methyl, ethyl, --(CH₂)_(n)--OH, wherein n is an integer from three to four, --CH₂ C.tbd.CH or R²and R³ are taken together with the nitrogen atoms to which they areattached to form a ring denoted by ##STR11## wherein n is zero or aninteger from one to six, ##STR12## wherein R⁷ is hydrogen or methyl.

Particularly valuable are:

Methyl[methyl4-(1-pyrrolidinyl)-2-butynyl]]carbamate;

Methyl methyl4-(1-piperidinyl)-2-butynyl]carbamate;

Methyl[4-(hexahydro-1H-azepin-1-yl)-2-butynyl]- methyl-carbamate;

Methyl[4-(dimethylamino)-2-butynyl]methylcarbamate;

Methyl[4-(ethyImethylamino)-2-butynyl]methylcarbamate;

Methyl[4-(1-pyrrolidinyl)-2-butynyl]-carbamate;

Methyl ethyl[4-(1-pyrrolidinyl)-2-butynyl]carbamate;

Ethyl[4-(1-pyrrolidinyl)-2-butynyl-carbamate;

Ethyl methyl[4-(1-pyrrolidinyl)-2-butynyl]carbamate;

Ethenyl methyl[4-(1-pyrrolidinyl)-2-butynyl)]carbamate;

Methyl4-(1-azetidinyl)-2-butynyl]methylcarbamate;

Methyl methyl[4-(4-morpholinyl)-2-butynyl]carbamate;

Methyl methyl[4-(4-methyl-1-piperazinyl)-2-butynyl]-carbamate;

Methyl methyl[4-(methylamino)-2-butynyl]carbamate;

Methyl[4-(diethylamino)-2-butynyl]methylcarbamate;

Methyl methyl4-[methyl(2-propynyl)amino]-2-butynyl]-carbamate;

Methyl[4-[(3-hydroxypropyl)methylamino]-2-butynyl]methyl-carbamate; and

Methyl[4-[(4-hydroxybutyl)methylamino]-2-butynyl]methyl-carbamate; or apharmaceutically acceptable acid addition salt thereof.

The compounds of Formula I are valuable centrally acting muscarinicagents. The biological activity of compounds of the present inventionwas evaluated using a number of tests. The activity of compounds of thepresent invention as central muscarinic binding site agonists andantagonists was measured. Thus, in the Receptor [³ H]QuinuclidinylBenzilate Binding Assay (RQNB), described more fully by Watson, M., etal, Journal of Pharmacology and Experimental Therapeutics, 237, pages411 to 418 (1986), rat cerebral cortex tissue is treated withradiolabeled quinuclidinyl benzilate, a known muscarinic binding siteantagonist. The concentration of test compound required to inhibit 50%of the binding of this muscarinic antagonist is then determined. Thisprocedure allows a determination of the affinity of the test compoundsfor the central muscarinic antagonist site. Similarly in the Receptor [³H]Cis-methyldioxalane Assay (RCMD), described more fully by Vickroy, T.W., et al, Journal of Pharmacology and Experimental Therapeutics, 229,pages 747 to 755 (1984), rat cerebral cortex tissue is treated withradiolabeled cis-methyldioxalane, a known muscarinic binding siteagonist. The concentration of test compound required to inhibit 50% ofthe binding of this muscarinic agonist is then determined. Thisprocedure allows a determination of the affinity of the test compoundfor the central muscarinic agonist site. The values for the RQNB andRCMD assay are shown in the table as IC₅₀ concentrations.

In the Muscarinic Induced Inositol Phosphate Accumulation Assay (MIPA)human SK-N-SH cells bearing muscarinic binding sites are incubated withthe test compound. The production of inositol phosphates is thenmeasured. Stimulation of inositol phosphate turnover reflects the degreeof muscarinic agonist activity of the test compound. The concentrationof test compound required to produce a response 50% of the maximum isthen determined.

    __________________________________________________________________________    Biological Activity of Compounds of Formula I                                                                       Agonist                                                                            Reversal of SIS                    Example                  RCMD  RQNB   Response                                                                           Hyperactivity                      Number                                                                             Compound            (0.1 μM)                                                                         (1 μM)                                                                            ED.sub.50                                                                          MED (mg/kg)                        __________________________________________________________________________    1    Methyl[methyl[4-(1-pyrrolidinyl)-2-                                                               14.3                                                                             nM 2660                                                                              nM 10.0 μM                                                                         10                                      butynyl]]-carbamate, ethanedioate                                             (1:1) (salt)                                                             1f   Methyl methyl[4-(1-piperidinyl)-2-                                                                1570                                                                             nM 4990                                                                              nM                                              butynyl]-carbamate, ethanedioate                                              (1:1) (salt)                                                             1g   Methyl[4-(hexahydro-1H-azepin-1-yl)-                                                              958                                                                              nM 1950                                                                              nM                                              2-butynyl]methyl-carbamate, ethane-                                           dioate (1:1) (salt)                                                      2    Methyl[4-(dimethylamino)-2-butynyl]-                                                              63 nM 46,600                                                                            nM 59.2 μM                                   methyl-carbamate ethanedioate (1:1) (salt)                               3b   Methyl[4-(ethylmethylamino)-2-butynyl]-                                                           84 nM 8840                                                                              nM                                              methyl-carbamate                                                         __________________________________________________________________________

In the Scopolamine Induced Swimming Assay (SIS) the ability of a testcompound to reverse the hyperactive swimming behavior of laboratory ratsgiven scopolamine is determined. In the assay, untreated rats generallyswim between 20 to 30 meters during a five-minute test period. Ratsgiven scopolamine at doses of 0.1 mg/kg develop a stereotypical swimminghyperactivity with the swimming distance generally increasing 75-125%above baseline values. This increase in swimming hyperactivity can bereversed by the administration of physostigmine or the cholinergicagonist, arecoline. The effect of scopolamine is centrally mediated.Thus, the ability of the test compound to reverse the hyperactiveswimming behavior induced by scopolamine is a measure of the centralcholinergic activity of the compound. The Minimal Effective Dose (MED)required for a compound to demonstrate reversal of the scopolamineinduced hyperactive swimming activity in laboratory rats is shown in thetable.

A compound of Formula I ##STR13## wherein R is alkyl of from one to sixcarbon atoms,

alkyl of from one to six carbon atoms substituted with hydroxy or alkoxyof from one to four carbon atoms,

alkenyl of from two to six carbon atoms,

alkenyl of from two to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkynyl of from two to six carbon atoms,

alkynyl of from two to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

cycloalkyl of from three to six carbon atoms, ##STR14## wherein n iszero or an integer of one to eight and R⁴ and R⁵ are independentlyhydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of from one tothree carbon atoms, or alkoxy of from one to four carbon atoms, or##STR15## wherein R⁴ and R⁵ are as defined above;

X is oxygen or sulfur;

R¹ is hydrogen,

alkyl of from one to six carbon atoms,

alkyl of from one to six carbon atoms substituted with hydroxy or alkoxyof from one to four carbon atoms,

alkenyl of from three to six carbon atoms,

alkenyl of from three to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkynyl of from three to six carbon atoms,

alkynyl of from three to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

cycloalkyl of from three to six carbon atoms, or ##STR16## wherein n, R⁴and R⁵ are as defined above: R² and R⁵ are each independently

hydrogen,

alkyl of from one to twenty carbon atoms,

alkyl of from one to twenty carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkenyl of from three to twenty carbon atoms,

alkenyl of from three to twenty carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

alkynyl of from three to twenty carbon atoms,

alkynyl of from three to twenty carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms,

cycloalkyl of from three to eight carbon atoms,

phenyl,

phenyl substituted with alkyl of from one to four carbon atoms, alkyl offrom one to four carbon atoms substituted with hydroxy or alkoxy of fromone to four carbon atoms, alkoxy of from one to four carbon atoms,chlorine, bromine, hydroxy, nitro or trifluoromethyl or

R² and R³ are taken together with the nitrogen atom to which they areattached to form a ring denoted by ##STR17## wherein R⁶ is hydrogen,alkyl of from one to ten carbon atoms, alkyl of from one to ten carbonatoms substituted with hydroxy or alkoxy of from one to four carbonatoms, alkenyl of from two to ten carbon atoms, alkenyl of from two toten carbon atoms substituted with hydroxy or alkoxy of from one to fourcarbon atoms, alkynyl of from two to ten carbon atoms or alkynyl of fromtwo to ten carbon atoms substituted with hydroxy or alkoxy of from oneto four carbon atoms and n is as defined above, ##STR18## wherein X isas defined above or ##STR19## wherein R⁷ is hydrogen or alkyl of fromone to six carbon atoms, or a pharmaceutically acceptable acid additionsalt thereof, may be prepared by reacting a compound of Formula II##STR20## wherein R, R¹, and X are as defined above with a compound ofFormula III ##STR21## wherein R² and R³ are as defined above in thepresence of paraformaldehyde, a catalyst such as, for example, cuprouschloride and the like and a solvent such as, for example, dioxane andthe like at about 25° C. to about the reflux temperature of the solventto give a compound of Formula I.

Additionally, a compound of Formula I may be prepared by reacting acompound of Formula II and a compound of Formula III in the presence ofan aqueous solution of formaldehyde, a catalyst such as, for example,cupric sulfate and the like and adjusting the pH to about 8.5 by theaddition of an aqueous solution of a base such as, for example, anaqueous solution of a compound of Formula III at about 25° C. to about100° C. to give a compound of Formula I.

A compound of Formula II ##STR22## wherein R, R¹, and X are as definedabove may be prepared by reacting a compound of Formula IV ##STR23##wherein HAL is a halogen atom and R and X are as defined above with acompound of Formula V ##STR24## wherein R¹ is as defined above in asolvent such as, for example, tetrahydrofuran and the like at about 25°C. to about the reflux temperature of the solvent to give a compound ofFormula II.

Alternatively, a compound of Formula 1 may be prepared by reacting acompound of Formula Vl ##STR25## wherein R, R¹, and X are as definedabove with a compound of Formula III to give a compound of Formula I.

A compound of Formula VI may be prepared by reacting a compound ofFormula I_(a) ##STR26## wherein R, R¹, and X are as defined above withcyanogen bromide in a solvent such as, for example, diethyl ether andthe like at about 25° C. to give a compound of Formula VI.

Compounds of Formula III, Formula IV and Formula V are either known orcapable of being prepared by methods known in the art.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of Formula I or acorresponding pharmaceutically acceptable salt of a compound of FormulaI.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.7 to 7000 mg depending upon the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

In therapeutic use as centrally active muscarinic agents the compoundsutilized in the pharmaceutical method of this invention are administeredat the initial dosage of about 0.01 to about 100 mg per kilogram daily.The dosages, however, may be varied depending upon the requirements ofthe patient, the severity of the condition being treated, and thecompound being employed. Determination of the proper dosage for aparticular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1 Methyl[methyl4-(1-pyrrolidinyl]-2-butynyl]]-carbamate,ethanedioate (1:1) (salt)

A solution of methyl N-methyl-N-(2-propynyl) carbamate (3.8 g, 0.03 mol)(Example A), paraformaldehyde (0.9 g, 0.03 mol), pyrrolidine (2.6 g,0.03 mol), and a spatula tip of cuprous chloride in 150 ml of anhydrousdioxane is allowed to reflux for two hours. After cooling the solutionis made strongly acidic with a 2 N solution of hydrochloric acid andwashed with diethyl ether. The aqueous solution is then made basic bythe addition of solid potassium carbonate until saturated, followed byextraction with diethyl ether (2X). The diethyl ether solution is driedover magnesium sulfate, filtered, and concentrated to afford a yellowoil. The oxalate salt is formed directly from this material; mp80°-83°C.

In a process analogous to Example 1 using appropriate starting materialsthe corresponding compounds of Formula I are prepared:

EXAMPLE 1a

Methyl[4-(1-pyrrolidinyl)-2-butynyl]-carbamate, ethanedioate (1:1)(salt); mp 129°-131° C.

EXAMPLE 1b

Methyl ethyl[4-(1-pyrrolidinyl]-2-butynyl]-carbamate; clear amberviscous liquid; Nuclear Magnetic Resonance (NMR)(CDCl₃): 4.11 (m, 2H);4.01 (m 4H); 3.15 (m, 4H); 2.84 (s, 3H); 1.88 (m, 4H); 1.16 (t, J =7.1Hz, 3H).

EXAMPLE 1c

Ethyl[4-(1-pyrrolidinyl)-2-butynyl]-carbamate ethanedioate (1:1) (salt);mp 90°-94° C.

EXAMPLE 1d

Ethyl methyl[4-(1-pyrrolidinyl)-2-butynyl]-carbamate, ethanedioate (1:1)(salt); mp 68°-70° C.

EXAMPLE 1e

Ethenyl methyl[4-(1-pyrrolidinyl]-2-butynyl]-carbamate, ethanedioate(1:1) (salt); mp 80°-82° C.

EXAMPLE 1f

Methyl methyl[4-(1-piperidinyl]-2-butynyl-carbamate, ethanedioate (1:1)(salt); mp 101°-102° C.

EXAMPLE 1g

Methyl[4-(hexahydro-1H-azepin-1-yl]-2-butynyl]methylcarbamate,ethanedioate (1:1) (salt); mp 98.5°-100° C.

EXAMPLE 1h

Methyl methyl4-(4-methyl-1-piperazinyl]-2-butynyl]carbamate,dihydrochloride; mp 192°-195° C. (d).

EXAMPLE 1i

Methyl[4-(diethylamino)-2-butynyl]methyl-carbamate, monohydrochloride;mp 88°-90° C.

EXAMPLE 1j

Methyl[4-(3-hydroxypropyl)methylamino]-2-butynyl]methyl-carbamate; cleargold viscous liquid. NMR(CDCl₃): 4.12 (brs, 2H); 3.79 (t, J =5.4 Hz,2H); 3.73 (s, 3H); 3.39 (t, J =1.9 Hz, 2H); 2.96 (brs, 3H); 2.67 (t, J=5.9 Hz, 2H); 2.33 (brs, 3H); 1.70 (m, 2H).

EXAMPLE 1k

Methyl[4[(4-hydroxybutyl)methylamino-2-butynyl]methyl-carbamate,ethanedioate (10:13) salt; clear gold viscous liquid. NMR(CDCl₃): 4.15(s, 2H); 4.04 (s, 2H); 3.72 (s, 3H); 3.65 (t, J =5.7 Hz, 2H); 3.23 (m,2H); 2.96 (s, 3H); 2.88 (s, 3H); 1.61-1.84 (m, 4H).

EXAMPLE 1l

Methyl methyl[4-(4-morpholinyl)-2-butynyl]-carbamate, ethanedioate (1:1)(salt); mp 109°-111° C.

EXAMPLE 2

Methyl[4-(dimethylamino)-2-butynyl]methyl-carbamate, ethanedioate(1:1)(salt)

A solution of 40% aqueous dimethylamine (5.6 ml, 0.05 mol) in water (60ml) is adjusted to pH 9 by addition of concentrated sulfuric acid.Formaldehyde (4.9 ml, 0.06 mol), methyl N-methyl-N(2-propynyl)carbamate(5.1 g, 0.04 mol) (Example A) and cupric sulfate (0.5 g) is added andthe pH adjusted to 8.5 by addition of aqueous dimethylamine. Thesolution is heated to 100° C. under a dry ice condenser for 2.5 hours.After cooling, the solution is allowed to stir overnight. The solutionis filtered through celite and made basic with solid potassiumcarbonate. The solution is extracted with chloroform (5×300 ml), driedover magnesium sulfate, and concentrated. The resulting oil is purifiedby bulb to bulb distillation under high vacuum and the ethanedioate saltformed; mp 84°-86° C.

EXAMPLE 3

Methyl[4-(1-azetidinyl]-2-butynyl]methyl-carbamate

A solution of methyl[4-(diethylamino)-2-butynyl]- methyl-carbamate (4.2g, 0.02 mol) (Example 1i) in anhydrous diethyl ether (50 ml) is addeddropwise at room temperature to a stirred solution of cyanogen bromidein anhydrous diethyl ether (40 ml). The mixture is allowed to stand for12 hours and the diethyl ether layer is separated, washed with water (40ml), dried over magnesium sulfate, and concentrated. The resulting oilis then purified by bulb to bulb distillation under high vacuum to givemethyl N-(4-bromo-2-butynyl)-N-methylcarbamate as a ight yellow oil.Azetidine (2 g, 0.032 mol) is added to a stirred solution of methylN-(4-bromo-2-butynyl)-N-methylcarbamate (3.6 g, 0.016 mol). The mixtureis kept at room temperature for one hour and then filtered. The filtrateis concentrated and the resulting oil purified by bulb to bulbdistillation under high vacuum to give a light yellow oil. NMR(CDCl₃):4.10 (brs, 2H); 3.7 (s, 3H); 3.39 (brs, 2H); 2.94 (s, 3H); 2.45 (brs,4H).

In a process analogous to Example 3 using appropriate starting materialsthe corresponding compounds of Formula I are prepared:

EXAMPLE 3a

Methyl methyl[4-(methylamino)-2-butynyl]-carbamate; yellow liquid.NMR(CDC₃): 4.07 (brs, 2H); 3.68 (s, 3H); 3.36 (t, J =1.9 Hz, 2H); 2.92(s, 3H); 2.42 (s, 3H); 1.5 (brs, 1H).

EXAMPLE 3b

Methyl[4-(ethylmethylamino]-2-butynyl]methyl-carbamate; yellow liquid.NMR(CDCl₃): 4.06 (brs, 2H); 3.66 (s, 3H); 3.27 (brs, 2H); 2.90 (s, H);2.29 (t, J =7.2 Hz, 2H); 2.23 (s, 3H); 1.00 (t, J =7.2 Hz, 3H).

EXAMPLE 3c

Methyl methyl[4-[methyl(2-propynyl)amino]-2-butynyl]carbamate; yellowliquid. NMR(CDCl₃): 4.12 (brs, 2H); 3.72 (s, 3H); 3.37 (s, 3H); 2.96 (s,4H); 2.37 (s, 3H); 2.25 (t, J =2.3 Hz, 1H).

PREPARATION OF STARTING MATERIAL

EXAMPLE A

Methyl N-methyl-N-(2-propynyl)carbamate

To a solution of triethylamine (75.8 g, 0.75 mol) andN-methylpropargylamine (50 g, 0.72 mol) in 750 ml of anhydroustetrahydrofuran is added dropwise methyl chloroformate (68.5 g, 0.72mol). The solution is allowed to reflux for one hour, cooled, wateradded, and the aqueous layer extracted with diethyl ether. The diethylether solution is dried over magnesium sulfate, filtered, andconcentrated to give 78.6 g of a light yellow oil. NMR(CDC₃): 4.15 (m,2H); 3.61 (s, 3H); 2.87 (s, 3H); 2.17 (m, 2H).

We claim:
 1. A compound of Formula I ##STR27## wherein R isalkyl of fromone to six carbon atoms, alkyl of from one to six carbon atomssubstituted with hydroxy or alkoxy of from one to four carbon atoms,alkenyl of from two to six carbon atoms, alkenyl of from two to sixcarbon atoms substituted with hydroxy or alkoxy of from one to fourcarbon atoms, alkynyl of from two to six carbon atoms, alkynyl of fromtwo to six carbon atoms substituted with hydroxy or alkoxy of from oneto four carbon atoms, cycloalkyl of from three to six carbon atoms,##STR28## wherein n is zero or an integer of one to eight and R⁴ and R⁵are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkylof from one to three carbon atoms, or alkoxy of from one to four carbonatoms, or ##STR29## wherein R⁴ and R⁵ are as defined above; X is oxygenor sulfur; R¹ isalkyl of from one to six carbon atoms, alkyl of from oneto six carbon atoms substituted with hydroxy or alkoxy of from one tofour carbon atoms, alkenyl of from three to six carbon atoms alkenyl offrom three to six carbon atoms substituted with hydroxy or alkoy of fromone to four carbon atoms, alkynyl of from three to six carbon atoms,alkynyl of from three to six carbon atoms substituted with hydroxy oralkoxy of from one to four carbon atoms, cycloalkyl of from three to sixcarbon atoms, or ##STR30## wherein n, R⁴ and R⁵ ar as defined above; R²and R³ are each independently hydrogen, alkyl of from one to twentycarbon atoms, alkyl of from one to twenty carbon atoms substituted withhydroxy or alkoxy of from one to four carbon atoms, alkenyl of fromthree to twenty carbon atoms, alkenyl of from three to twenty carbonatoms substituted with hydroxy or alkoxy of from one to four carbonatoms, alkynyl of from three to twenty carbon atoms, alkynyl of fromthree to twenty carbon atoms substituted with hydroxy or alkoxy of fromone to four carbon atoms, cycloalkyl of from three to eight carbonatoms, phenyl, phenyl substituted with alkyl of from one to four carbonatoms, alkyl of from one to four carbon atoms substituted with hydroxyor alkoxy of from one to four carbon atoms, alkoxy of from one to fourcarbon atoms, chlorine, bromine, hydroxy, nitro or trifluoromethyl or R²and R³ are taken together with the nitrogen atom to which they areattached to form a ring denoted by ##STR31## wherein R⁶ is hydrogen,alkyl of from one to ten carbon atoms, alkyl of from one to ten carbonatoms substituted with hydroxy or alkoxy of from one to four carbonatoms, alkenyl of from two to ten carbon atoms, alkenyl of from two toten carbon atoms substituted with hydroxy or alkoxy of from one to fourcarbon atoms, alkynyl of from two to ten carbon atoms or alkynyl of fromtwo to ten carbon atoms substituted with hydroxy or alkoxy of from oneto four carbon atoms and n is as defined above, ##STR32## wherein X isas defined above or ##STR33## wherein R⁷ is hydrogen or alkyl of fromone to six carbon atoms, or a pharmaceutically acceptable acid additionsalt thereof.
 2. A compound according to claim 1, in whichR isalkyl offrom one to six carbon atoms, or alkenyl of from two to six carbonatoms; X is oxygen; R¹ is alkyl of from two to six carbon atoms; R² andR³ are each independentlyhydrogen, alkyl of from one to twenty carbonatoms, alkyl of from one to twenty carbon atoms substituted with hydroxyor alkoxy of from one to four carbon atoms, alkenyl of from three totwenty carbon atoms, alkynyl of from three to twenty carbon atoms or R²and R³ are taken together with the nitrogen atom to which they areattached to form a ring denoted by ##STR34## wherein n is zero or aninteger from one to eight, ##STR35## wherein X is oxygen or sulfur or##STR36## wherein R⁷ is hydrogen or alkyl of from one to six carbonatoms.
 3. A compound according to claim 2, in whichR ismethyl, ethyl, orethenyl; X is oxygen; R¹ is methyl, or ethyl; R² and R³ are eachindependently hydrogen, methyl, ethyl, --(CH₂)_(n) --OH, wherein n is anintenger from three to four, --CH₂ C.tbd.CH or R² and R³ are takentogether with the nitrogen atoms to which they are attached to form aring denoted by ##STR37## wherein n is zero or an integer from one tosix, ##STR38## wherein R⁷ is hydrogen or methyl.
 4. A compound accordingto claim 3, selected from the group consistingof:methyl[methyl[4-(1-pyrrolidinyl)-2-butynyl]]carbamate; methylmethyl[4-(1-piperidinyl)-2-butynyl]carbamate;methyl[4-(hexahydro-1H-azepin-1-yl)-2-butynyl]methyl-carbamate;methyl[4-(dimethylamino)-2-butynyl]methylcarbamate;methyl[4-(ethylmethylamino)-2-butynyl]methyl-carbamate; methylethyl[4-(1-pyrrolidinyl)-2-butynyl]carbamate; ethylmethyl[4-(1-pyrrolidinyl)-2-butynyl)]carbamate; ethenylmethyl[4-(1-pyrrolidinyl)-2-butynyl)]carbamate;methyl[4-(1-azetidinyl)-2-butynyl]methyl-carbamate; methylmethyl[4-(4-morpholinyl)-2-butynyl]carbamate; methylmethyl[4-(4-methyl-1-piperazinyl) 2-butynyl]-carbamate; methylmethyl[4-(methylamino)-2-butynyl]carbamate;methyl[4-(diethylamino)-2-butynyl]methylcarbamate; methyl methyl[4-methyl(2-propynyl)amino]2-butynyl]-carbamate;methyl[4-[(3-hydroxypropyl)methylamino]2-butynyl]methyl-carbamate; andmethyl[4-[(4-hydroxybutyl)methylamino]2-butynyl]methyl-carbamate.
 5. Amethod of treating the symptoms of cognitive decline in an elderlypatient comprising a cholinergically effective amount of a compoundaccording to claim
 1. 6. A pharmaceutical composition for the treatmentof the symptoms of cognitive decline in an elderly patient comprising acholinergically effective amount of a compound according to claim 5 incombination with a pharmaceutically acceptable carrier.